The present invention relates to the filtration of macromolecules from fluids, and more particularly to the removal of undesirable macromolecules from plasma solutions, by the process termed thermofiltration.
The separation of undesirable solutes from blood plasma through plasma filtration is a known method of treating diseases, wherein such diseases have in common undesirable elevated levels of plasma solutes, such as toxins, excessive antibodies, and other metabolic factors. Successful treatment of such diseases involves the removal of the undesirable plasma solutes from the blood plasma by membrane filtration.
Various methods of plasma filtration, including cascade filtration, double filtration, and cryofiltration have been developed. However, these methods contain a number of undesirable characteristics which limit their usage.
Applicants have noted a number of parameters associated with performance, including module design, membrane properties, plasma composition, and plasma and filtration temperature. Characteristics of the module which affect flow dynamics and in turn performance include, area, fluid and film dimensions, as well as properties of the separating membrane, including polymer type and microstructural features such as pore size, pore tortuosity, pore length, and pore number.
Variations in the plasma's composition also affects its filtration. Plasma from patients with different disease states or with differing macromolecule contents have different filtration characteristics. Manipulation of the plasma to effect changes in pH or electrolyte composition and the addition of anticoagulants such as heparin or other macromolecule-aggregating additives such as polyethylene glycol will effect filtration performance. Generally such manipulations are carried out for the purpose of augmenting the separation, by macromolecule aggregation or precipitation, of one or a group of solutes from the plasma.
Because of the number of parameters affecting filtration performance, temperature selection and its control has been demonstrated to be a key parameter in fluid separation. In order to augment the selective removal in a particular macromolecular range, it is extremely important to operate within the proper temperature range. In this respect, significant differences have been noted for comparable conditions of filtration (similar operating flows, modular types and plasma types) between cascade and double filtration, which operate at near ambient temperatures, and cryofiltration, which operates at temperatures below a set physiologic temperature.
Temperature control offers many advantages over the other parameters in that temperature control is the easiest controlled physical parameter, and that temperature control may be combined with the use of various complexing agents to increase the sensitivity of macromolecule removal. A specific example of this can be shown in the case of cryofiltration, where the addition of heparin aids in the formation of cryogel by forming complexes with fibronectin and fibrinogen at temperatures below 25.degree. C.
Filtration at sub-physiologic temperature is effective for the removal of plasma constituents similar in size but differing in temperature sensitivity. A number of autoimmune diseases can be treated in this fashion, as has been described in the literature. The effectiveness of the treatment is attributed to the formation and removal of cryogel, which is composed of high concentrations of the macromolecules associated with autoimmune disease states. Thus, the separation in cryofiltration is not based on molecular size at physiologic temperature but on molecular size at reduced temperatures.
However, operation at a reduced temperature can, in fact, reduce the selectivity of molecule separation when size differences are great since aggregation or complex formation of small molecules may also occur at reduced temperatures. Therefore, for separation based on size differences at physiologic temperatures, it may be more advantageous to avoid cryogel formation.
Accordingly, it is an object of the present invention to provide an improved means of removing undesirable macromolecules from fluids in an effective and efficient manner.